2. Academic Validation
  3. A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration

A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration

  • Nat Commun. 2018 May 17;9(1):1976. doi: 10.1038/s41467-018-04261-1.
Yuanyuan Chen 1 2 3,  Yu Chen 4 5,  Beata Jastrzebska 4 6,  Marcin Golczak 4 6,  Sahil Gulati 4 6,  Hong Tang 7,  William Seibel 7,  Xiaoyu Li 4,  Hui Jin 4,  Yong Han 8,  Songqi Gao 4,  Jianye Zhang 4,  Xujie Liu 9,  Hossein Heidari-Torkabadi 4,  Phoebe L Stewart 4 6,  William E Harte 10,  Gregory P Tochtrop 8,  Krzysztof Palczewski 11 12
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. cheny1@pitt.edu.
  • 2 The McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive Suite 300, Pittsburgh, PA, 15219, USA. cheny1@pitt.edu.
  • 3 Department of Ophthalmology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. cheny1@pitt.edu.
  • 4 Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
  • 5 Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 200437, Shanghai, China.
  • 6 Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 E. 101st Street, Cleveland, OH, 44106, USA.
  • 7 Drug Discovery Center, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, OH, 45237, USA.
  • 8 Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
  • 9 Department of Ophthalmology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA.
  • 10 Office of Translation and Innovation, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
  • 11 Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. kxp65@case.edu.
  • 12 Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 E. 101st Street, Cleveland, OH, 44106, USA. kxp65@case.edu.
PMID: 29773803 DOI: 10.1038/s41467-018-04261-1
Abstract

Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity. YC-001 binds to bovine rod opsin with an EC50 similar to 9-cis-retinal. The chaperone activity of YC-001 is evidenced by its ability to rescue the transport of multiple rod opsin mutants in mammalian cells. YC-001 is also an inverse agonist that non-competitively antagonizes rod opsin signaling. Significantly, a single dose of YC-001 protects Abca4 -/- Rdh8 -/- mice from bright light-induced retinal degeneration, suggesting its broad therapeutic potential.

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